Download Bio 347 Ch 12 Cytokines

Bio 347 Ch 12 Cytokines
I. Cytokines and Receptors:
1. cyokines are small (8-80 kDa) protein signaling molecules (over 200 different human cytokines-gene families)
2. cytokines are transient and act over short distances , autocrine (cells that produce them) and paracrine
(acting on cells close by) rather than endocrine (acting on cells at a distance)
3. cytokines regulate expression of own receptor or other cytokine receptors
4. many cytokines act by causing aggregation of receptors at the cell surface
5. Cytoknes act synergistically or antagonistically (bind receptor-no response)
6. T helper cells are divided into T helper 1 and T helper 2 on basis of cytokine production
7. T helper 1 cells can down-regulte T helper 2 cells and vice versa
8. cytokines act in a network (immune response is dependent on pattern of cytokines a cell is exposed to
and receptors the cell expresses).
II. Families of cytokines:
1. interleukins (IL-1, etc), 2. interferons (IFN, 50 family members); 3. tumor necrosis factors
(TNF); 4. growth factors (EGF, IGF, etc); 5. colony stimulating factors (CSF); 6. chemokines
(IL-8, etc)
III. Cytokines can have many functions
1. TNF-as an example--perhaps as many as 30 members of TNF- family: defense against
intracellular pathogens, co-mitogen for T and B cells, induces other cytokines, regulastes hematopoiesis,
induces growth factors, activates macrophages
III. Cytokine receptors:
(family based on 3-dimentional structure and limited sequence homology); common characteristics
include: consist of two or more subunits, share common subunits. Belong to seven transmembrane
domain family.
1. Ig superfamily receptors (IL-1, IL-2--IL-1 on many cell types, IL-2 limited to B cells)
2. Type 1 (hematopoietin) receptors: IL-2-7, IL-9, IL-12, colony stimulating factors (granulocyte-GCSF and granulocyte/macrophage GM-CSF).
3. Type 2 (interferon) receptors: (belong to Ig super family): All IFN, IL-10, and M-CSF
4. Type 3 (TNF) receptors:, Fas, DR4/DR5 (TRAIL), CD40--acts as co-stimulatory molecule as well as
cytokine receptor
5. Type 4 (Chemokine) IL-8
IV. Mechanisms of cell activation:
Cascade of that leads to activation or inhibition of transcription factors
1. MAP kinase (ERK) and PI-3 kinase (AKT) pathways are involved in cell proliferation
2. Type 1 cytokine receptors activate Janus kinases (JAKs) and STATs--NF-kB as an example
V. Cytokine production by T-cell subsets
(T cell subsets based on cytokine production; however, recent studies show cell surface marker
differences; TH1--CD26/LAG-3, CCR5; TH2--CCR3 and CCR4)
1. T helper 1 cells: IL-2, IFN-, TNF-, IL-3
2. T helper 2 cells: IL-4-6, IL-9-10, IL-13
VII. Factors that influence differentiation of T helper 1 or T helper 2 cells (cytokine environment)
1. the cytokine profile and balance of cytokines evoked by antigen (example, IL-12 stimulates IFN- ,
regulating TH1 cells), 2. high MHC class II peptide density favors TH1 cells, 3. local environment
provided co-stimulatory molecules and hormones, 4. genetic background; 5. Properties and dosage of
immunogen
VIII. Cytokine related diseases
1. Bacterial septic shock: Bacterial cell wall endotoxins bind TLRs on dendritic cells and macrophages,
overproduce IL-1 and TNF- . "Sepsis" caused by over production of TNF- and IL-1
2. Bacterial toxic shock can be caused by superantigens--T cells express TNF- and IL-1
IX. Cytokine-based therapies